This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fVIIa, flXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin). In another aspect, the present invention relates to novel monoamidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals. In yet another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders.
Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfumction or other disruption. Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition.
Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., xe2x80x9cSynthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation Systemxe2x80x9d, Blood Coag. Fibrinol. 5, 411-436 (1994). Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins).
A prothrombinase complex, including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin. Unlike thrombin, which acts on a variety of protein substrates as well as at a specific receptor, factor Xa appears to have a single physiologic substrate, namely prothrombin. Since one molecule of factor Xa may be able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. 15, 617-619 (1979)), direct inhibition of factor Xa as a way of indirectly inhibiting the formation of thrombin may be an efficient anticoagulant strategy. Therefore, it has been suggested that compounds which selectively inhibit factor Xa may be useful as in vitro diagnostic agents, or for therapeutic administration in certain thrombotic disorders, see e.g., WO 94/13693.
Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa. U.S. Pat. No. 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al., xe2x80x9cThe Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structurexe2x80x9d, J. Biol. Chem., 20, 10162-10167 (1988). Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al., xe2x80x9cTick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xaxe2x80x9d Science, 248, 593-596 (1990).
Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R. R. et al., xe2x80x9cStrategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitorsxe2x80x9d, Thromb. Res., 19, 339-349 (1980); Turner, A. D. et al., xe2x80x9cp-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombinxe2x80x9d, Biochemistry, 25, 4929-4935 (1986); Hitomi, Y. et al., xe2x80x9cInhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation Systemxe2x80x9d, Haemostasis, 15, 164-168 (1985); Sturzebecher, J. et al., xe2x80x9cSynthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiencyxe2x80x9d, Thromb. Res., 54, 245-252 (1989); Kam, C. M. et al., xe2x80x9cMechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulantsxe2x80x9d, Biochemistry, 27, 2547-2557 (1988); Hauptmann, J. et al., xe2x80x9cComparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitorsxe2x80x9d, Thromb. Haemost., 63, 220-223 (1990); and the like.
Others have reported Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(xe2x95x90NH)xe2x80x94NH2 group; WO 97/21437 describes benzimidazole compounds substituted by a basic radical which are connected to a naththyl group via a straight or branched chain alkylene,xe2x80x94C(xe2x95x90O) or xe2x80x94S(xe2x95x90O)2 bridging group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N-alkylamidino-piperidine group connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group.
There exists a need for effective therapeutic agents for the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. In particular, there continues to be a need for compounds which selectively inhibit factor Xa or its precursors. Compounds that have different combinations of bridging groups and functional groups than compounds previously discovered are needed, particularly compounds which selectively or preferentially bind to Factor Xa. Compounds with a higher degree of binding to Factor Xa than to thrombin are desired, especially those compounds having good bioavailability and/or solubility.
The present invention relates to novel compounds which inhibit factor Xa, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals. In another aspect, the invention relates.to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals which have coagulation disorders, such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples.
In certain embodiments, this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
In a preferred embodiment, the present invention provides a compound of the formula I:
Axe2x80x94Yxe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Jxe2x80x94Zxe2x80x94L
wherein:
A is selected from:
(a) C1-C6-alkyl;
(b) C3-C8-cycloalkyl;
(c) phenyl, which is independently substituted with 0-2 R1 substituents;
(d) naphthyl, which is independently substituted with 0-2 R1 substituents; and
(e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1 substituents;
R1 is selected from:
Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3 8-cycloalkyl, xe2x80x94CN, xe2x80x94NO2, (CH2)mNR2R3, SO2NR2R3, SO2R2, CF3, OR2, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, xe2x80x94CN C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C1-8cycloalkyl, C1-4alkylC3-8cycloalkyl and xe2x80x94NO2;
R2 and R3 are independently selected from the group consisting of:
H, C1-4alkyl, C2-6alkenyl, C2-4alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-4alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
m is an integer of 0-2;
Y is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94N(R4)xe2x80x94 and xe2x80x94N(R4)xe2x80x94SO2xe2x80x94;
R4 is selected from:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
D is a direct link or is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1a substituents;
(b) naphthyl, which is independently substituted with 0-2 R1a substituents; and
(c) amonocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1a substituents;
R1a is selected from:
Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8-cycloalkyl, xe2x80x94CN, xe2x80x94NO2, (CH2)mNR2aR3a, SO2NR2aR3a, SO2R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2; 
R2a and R3a are independently selected from the group consisting of:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C1-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
E is a member selected from the group consisting of:
xe2x80x94N(R5)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R5)xe2x80x94, xe2x80x94N(R5)xe2x80x94C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94, xe2x80x94SO2xe2x80x94N(R5)xe2x80x94, xe2x80x94N(R5)xe2x80x94SO2xe2x80x94N(R6)xe2x80x94 and xe2x80x94N(R5)xe2x80x94SO2xe2x80x94N(R6)xe2x80x94C(xe2x95x90O)xe2x80x94;
R5 and R6 are independently selected from:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl, C1-4alkylnaphthyl, C0-4alkylheteroaryl, C1-4alkylCOOH and C1-4alkylCOOC1-4alkyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
G is selected from:
xe2x80x94CR7R8xe2x80x94 and CR7aR8axe2x80x94CR7bR8bxe2x80x94
wherein R7, R8, R7a, R8a, R7a and R8b are independently a member selected from from the group consisting of:
hydrogen, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl xe2x80x94C0-4alkylCOOR9, xe2x80x94C0-4alkylC(xe2x95x90O)NR9R10, xe2x80x94C0alkylC(xe2x95x90O)NR9xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94R10, xe2x80x94C0-4alkylC(xe2x95x90O)NR9(xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94R10xe2x80x94)2, xe2x80x94N(R9)COR10, xe2x80x94N(R9)C(xe2x95x90O)R10, xe2x80x94N(R9)SO2R10, and a naturally occurring or synthetic amino acid side chain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
R9 and R10 are independently selected from:
H, C1-4alkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2, and wherein R9 and R10 taken together can form a 5-8 membered heterocylic ring;
J is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94N(R11)xe2x80x94(CH2)0-2, xe2x80x94N(R11)xe2x80x94(CH2)0-2xe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94N(R11)xe2x80x94(CH2)0-2;
R11 is a member selected from the group consisting of:
hydrogen, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC1-4alkyl, CH2COOC1-4alkylphenyl and CH2COOC1-4alkylnaphthyl;
Z is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1b substituents;
(b) naphthyl, which is independently substituted with 0-2 R1b substituents; and
(c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1b substituents;
R1b is selected from:
Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, xe2x80x94NO2, NR2bR3b, SO2NR2bR3b, SO2R2b, CF3, OR2b, Oxe2x80x94CH2-Ph, Oxe2x80x94CH2xe2x80x94OPh, Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b, Oxe2x80x94CH2COOR2b, N(R2b)xe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b, N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OR2 )2, N(R2b)xe2x80x94C(xe2x95x90O)R3b, N(R2b)xe2x80x94SO2R3b, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-4alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
R2b and R3b are independently selected from the group consisting of:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C1-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
L is selected from:
H, xe2x80x94CN, C(xe2x95x90O)NR12R13, (CH2)nNR12R13, C(xe2x95x90NR12)NR12R13, OR12, NR12R13, xe2x80x94NR12C(xe2x95x90NR12)NR12R13, and NR12C(xe2x95x90NR12)xe2x80x94R13;
R12 and R13 are independently selected from:
hydrogen, xe2x80x94OR14, xe2x80x94NR14R15, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, COOC1-4alkyl, COOxe2x80x94C0-4alkylphenyl and COOxe2x80x94C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
R14 and R15 are independently selected from:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In certain aspects of this invention, compounds are provided which are useful as diagnostic reagents. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In yet another aspect, the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesired thrombosis or disorders of the blood coagulation process in mammals, or for preventing coagulation in biological samples such as, for example, stored blood products and samples. Optionally, the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
The preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term xe2x80x9calkenylxe2x80x9d refers to a trivalent straight chain or branched chain unsaturated aliphatic radical. The term xe2x80x9calkinylxe2x80x9d (or xe2x80x9calkynylxe2x80x9d) refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
The term xe2x80x9calkylxe2x80x9d refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.
As used herein, the terms xe2x80x9ccarbocyclic ring structurexe2x80x9d and xe2x80x9cC3-16carbocyclic mono, bicyclic or tricyclic ring structurexe2x80x9d or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is aromatic ring (xe2x80x9carylxe2x80x9d) having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein the tricyclic ring structure is selected from the group consisting of: ring structures in which three of the rings are aromatic, ring structures in which two of the rings are aromatic and ring structures in which three of the rings are non-aromatic. In each case, the non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated. Examples of such carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure. The term xe2x80x9csubstitutedxe2x80x9d as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution(s) would result in a stable compound.
The term xe2x80x9carylxe2x80x9d which is included with the term xe2x80x9ccarbocyclic ring structurexe2x80x9d refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
The term xe2x80x9carylalkylxe2x80x9d which is included with the term xe2x80x9ccarbocyclic arylxe2x80x9d refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
As used herein, the term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclic ring systemxe2x80x9d is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S. Any nitrogen and sulfur atoms present in a heterocyclic ring of such a heterocyclic ring structure may be oxidized. Unless indicated otherwise the terms xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclic ring systemxe2x80x9d include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings. Also, unless indicated otherwise the term xe2x80x9cheterocyclic ring systemxe2x80x9d includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term xe2x80x9cheterocyclic ring systemsxe2x80x9d as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom. Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure. Further, the term xe2x80x9csubstitutedxe2x80x9d means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound. Nitrogen atoms in a ring structure may be quaternized, but such compounds are specifically indicated or are included within the term xe2x80x9ca pharmaceutically acceptable saltxe2x80x9d for a particular compound. When the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure.
Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuiranyl, isochromanyl, isoindazolyl, isoindolinyi, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl,. purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuiranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring structures.
As used herein the term xe2x80x9caromatic heterocyclic ring systemxe2x80x9d has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refer to Cl, Br, F or I substituents. The term xe2x80x9chaloalkylxe2x80x9d, and the like, refer to an aliphatic carbon radicals having at least one hydrogen atom replaced by a Cl, Br, F or I atom, including, mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example.
The term xe2x80x9cmethylenexe2x80x9d refers to xe2x80x94CH2xe2x80x94.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both acid and base addition salts are within the scope of the present invention. xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
xe2x80x9cPharmaceutically acceptable base addition saltsxe2x80x9d include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
xe2x80x9cBiological propertyxe2x80x9d for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector ftmctions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
In the compounds of this invention, carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
In a preferred embodiment, the present invention provides a compound according to the formula I:
Axe2x80x94Yxe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Jxe2x80x94Zxe2x80x94L
wherein:
A is selected from:
(a) C1-C6-alkyl;
(b) C3xe2x80x94C8-cycloalkyl;
(c) phenyl, which is independently substituted with 0-2 R1 substituents;
(d) naphthyl, which is independently substituted with 0-2 R1 substituents; and
(e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1 substituents;
R1 is selected from:
halo, C1-4alkyl, xe2x80x94CN, (CH2)mNR2R3, SO2NR2R3, SO2R2, CF3, OR2, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S;
R2 and R3 are independently selected from the group consisting of:
H, C1-4alkyl and C0-4alkylaryl,
m is an integer of 0-2;
Y is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94N(R4)xe2x80x94 and xe2x80x94N(R4)xe2x80x94SO2xe2x80x94;
R4 is selected from:
H, C1-4alkyl and C0-4alkylaryl;.
D is absent or is a member selected from the group consisting of:
(a) aryl, which is independently substituted with 0-2 R1a substituents; and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1a substituents;
R1a is selected from:
Halo, C1-4alkyl, xe2x80x94CN, xe2x80x94NO2, (CH2)mNR2R3a, SO2NR2aR3a, SO2R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatoms selected from N, O and S;
R2a and R3a are independently selected from the group consisting of:
H, C1-4alkyl and C1-4alkylaryl;
E is a member selected from the group consisting of: xe2x80x94N(R5)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R5)xe2x80x94, xe2x80x94N(R5)xe2x80x94C(xe2x95x90O)xe2x80x94N(R6)xe2x80x94, xe2x80x94SO2xe2x80x94N(R5)xe2x80x94, xe2x80x94N(R5)xe2x80x94SO2xe2x80x94N(R6)xe2x80x94 and xe2x80x94N(R5)xe2x80x94SO2xe2x80x94N(R6)C(xe2x95x90O)xe2x80x94;
R1 and R6 are independently selected from:
H, C1-4alkyl, C0-4alkylaryl, C0-4alkylheteroaryl, C1-4alkylCOOH and C1-4alkylCOOC1-4alkyl;
G is selected from:
xe2x80x94CR7R8xe2x80x94 and CR7aR8aCR7bR8bxe2x80x94
wherein R7, R8, R7a, R8a, R7b and R8b are independently a member selected from from the group consisting of:
hydrogen, C1-4alkyl, C1-4alkyl-C3-8cycloalkyl, C0-4alkylaryl, xe2x80x94C1-4alkylCOOR9, xe2x80x94C0-4alkylC(xe2x95x90O)NR9R10, xe2x80x94N(R9)COR10, xe2x80x94N(R9)C(xe2x95x90O)R10, xe2x80x94N(R9)SO2R10, and common amino acid side chains;
R9 and R10 are independently selected from:
H, C1-4alkyl and C0-4alkylaryl;
J is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94N(R11)xe2x80x94(CH2)0-2, xe2x80x94N(R11)xe2x80x94(CH2)0-2xe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94N(R11)xe2x80x94(CH2)0-2;
R11 is a member selected from the group consisting of:
hydrogen, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylkaryl, C0-4alkylheterocyclics, CH2COOC1-4alkyl, CH2COOC1-4alkylaryl;
Z is a member selected from the group consisting of:
(a) aryl, which is independently substituted with 0-2 R1b substituents;and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1b substituents;
R1b is selected from:
halo, C1-4alkyl, xe2x80x94CN, xe2x80x94NO2, NR2bR3b, SO2NR2bR3b, SO2OR2bR3b, CF3, OR2b, Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b, Oxe2x80x94CH2COOR2b, N(R2b)xe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b, N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b)2, N(R2b)C(xe2x95x90O)R3b, N(R2b)xe2x80x94SO2R3b, and a 5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatoms selected from N, O and S;
R2b and R3b are independently selected from the group consisting of:
H, C1-4alkyl and C0-4alkylaryl;
L is selected from:
H, xe2x80x94CN, C(xe2x95x90O)NR12R13, (CH2)nNR12R13, C(xe2x95x90NR12)NR12R13, OR12, xe2x80x94NR12C(xe2x95x90NR12)NR12R13 and NR12C(xe2x95x90NR12)xe2x80x94R13;
R12 and R13 are independently selected from: hydrogen, xe2x80x94OR14, xe2x80x94NR14R15, C1-4alkyl, C0-4alkylaryl COOC1-4alkyl, and COOxe2x80x94C0-4alkylaryl;
R14 and R15 are independently selected from:
H and C1-4alkyl; and
all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In a further preferred embodiment, the present invention provides a compound according to the formula I:
Axe2x80x94Yxe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Jxe2x80x94Zxe2x80x94L
wherein:
A is selected from:
(a) phenyl, which is independently substituted with 0-2 R1 substituents; and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1 substituents;
R1 is selected from:
halo, (CH2)mNR2R3, SO2NR2R3 and SO2R2;
R2 and R3 are independently selected from the group consisting of:
H and C1-4alkyl;
Y is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94 and xe2x80x94Oxe2x80x94;
D is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1a substituents; and
(b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be subsituted from 0-2 R1a substituents;
R1a is selected from:
Halo and C1-4alkyl;
R2a and R3a are independently selected from the group consisting of:
H, C1-4alkyl, C0-4alkylaryl;
E is a member selected from the group consisting of:
xe2x80x94N(R5)xe2x80x94C(xe2x95x90O)xe2x80x94 and xe2x80x94C(xe2x95x90O)xe2x80x94N(R5)xe2x80x94;
R1 and R6 are independently selected from:
H, C1-4alkyl, C1-4alkylaryl and C0-4alkylheteroaryl;
G is selected from:
xe2x80x94CR7R8xe2x80x94 and xe2x80x94CR7aR8axe2x80x94CR7bR8bxe2x80x94
wherein R7, R78, R7a, R8a, R7b and R8b are independently a member selected from from the group consisting of:
hydrogen, C1-4alkyl, C0-4alkyl-C3-8cycloalkyl, C1-4alkylaryl, xe2x80x94C0-4alkylCOOR9, xe2x80x94C0-4alkylC(xe2x95x90O)NR9R10, C0-4alkylC(xe2x95x90O)NR9xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94R10, xe2x80x94C0-4alkylC(xe2x95x90O)NR9(xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94R10xe2x80x94)2, xe2x80x94N(R9)COR10, xe2x80x94N(R9)C(xe2x95x90O)R10, xe2x80x94N(R9)SO2R10, and common amino acid side chains;
R9 and R10 are independently selected from:
H and C1-4alkyl, wherein the NR9R10 group of R7, R8, R7a, R8a, R7b and R8b is optionally cyclized to form a 5-8 membered heterocyclic group;
J is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94N(R11)xe2x80x94(CH2)0-2, xe2x80x94N(R11)xe2x80x94(CH2)0-2xe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94N(R11)xe2x80x94(CH2)0-2;
R11 is a member selected from the group consisting of:
hydrogen, C1-4alkyl, C2-6alkenyl, C0-4alkylaryl and a C1-4alkylheterocyclic ring;
Z is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1b substituents;
(b) an aromatic heterocyclic ring having from 5 to 10 ring atoms, wherein 1-4 ring atoms are selected from N, O and S, and wherein the ring may be subsituted independently by from 0-2 R1b substituents; and
(c) a fused aromatic bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, wherein the bicyclic ring system may be subsituted from 0-2 R1b substituents;
R1b is selected from:
halo, C1-4alkyl, OH, OBn, Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OH, Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OCH3, Oxe2x80x94CH2xe2x80x94COOH, Oxe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH3, NH2, NHxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, NHxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94CH3, and NHxe2x80x94SO2xe2x80x94CH3;
L is selected from:
H, C(xe2x95x90O)NR12R13, (CH2)nNR12R13 and C(xe2x95x90NR12)NR12R13;
R12 and R13 are independently selected from:
hydrogen and C1-4alkyl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In a further preferred embodiment, the present invention provides a compound according to formula I:
Axe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Jxe2x80x94Zxe2x80x94L
Wherein:
A is a member selected from the group consisting of: 
D is a member selected from the group consisting of: 
E is a member selected from the group consisting of:
xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(xe2x80x94CH3)xe2x80x94, C(xe2x95x90O)xe2x80x94N(-Bn)xe2x80x94, xe2x80x94NHxe2x80x94C(xe2x80x94O)xe2x80x94, xe2x80x94N(xe2x80x94CH3)C(xe2x95x90O)xe2x80x94 and xe2x80x94N(-Bn)C(xe2x95x90O)xe2x80x94;
G is selected from:
xe2x80x94CH(xe2x80x94NH2)xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x80x94(xe2x80x94NH(C(xe2x95x90O)xe2x80x94CH3))xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x80x94(xe2x80x94NH(C(xe2x95x90O)-Ph))xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x80x94(C(xe2x95x90O)xe2x80x94OR8)xe2x80x94, xe2x80x94CH(xe2x80x94R7)xe2x80x94, xe2x80x94CH2xe2x80x94CH(C(xe2x95x90O)xe2x80x94OR8)xe2x80x94, and xe2x80x94CH2xe2x80x94CH(C(xe2x95x90O)xe2x80x94N(xe2x80x94R8, xe2x80x94R8))xe2x80x94;
R7 is a member selected from the group consisting of:
H, phenyl, Bn, and cycohexyl;
R8 is a member selected from the group consisting of:
H, C1-6alkyl, and C3-6cycloalkyl;
J is a member selected from the group consisting of;
xe2x80x94C(xe2x95x90O)xe2x80x94N(R11)xe2x80x94(CH2)0-2, xe2x80x94N(R11)xe2x80x94(CH2)0-2xe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94N(R11)xe2x80x94(CH2)0-2;
R11 is a member selected from the group consisting of:
H, methyl, phenyl and benzyl; and
Z and L taken together are a member selected from the group consisting of: 
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
The following non-limiting tables illustrate representative compounds of the present invention:
wherein R3 is a member selected from the group consisting of H, F, xe2x80x94OH, Br, Cl, xe2x80x94NH2, xe2x80x94Oxe2x80x94CH2xe2x80x94O-Ph and xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3,
This invention also encompasses all pharmaceutic ally acceptable isomers, salts, hydrates and solvates of the compounds of formulas I, II and III. In addition, the compounds of formulas I, II and III can exist in various isomeric and tautomeric forms, and all such forms are meant to be included in the invent ion, along with pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers.
The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids hand bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, the free acid or free base form of a compound of one of the formulas above can be reacted with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
Prodrug Derivatives of Compounds
This invention also encompasses prodrug derivatives of the compounds contained herein. The term xe2x80x9cprodrugxe2x80x9d refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransfornation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of fanctionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
As mentioned above, the compounds of this invention find utility as therapeutic agents for disease states in mammals which have disorders of coagulation such as in the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic stroke, embolic stroke, disseminated intravascular coagulation including the treatment of septic shock, deep venous thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries. Further, these compounds are useful for the treatment or prophylaxis of those diseases which involve the production and/or action of factor Xa/prothrombinase complex. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include but are not limited to, deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery and peripheral arterial occlusion.
Accordingly, a method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprises administering to the mammal a therapeutically effective amount of a compound of this invention. In addition to the disease states noted above, other diseases treatable or preventable by the administration of compounds of this invention include, without limitation,: occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty, thrombus formation in the venous vasculature, disseminated intravascular coagulopathy, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure, hemorrhagic stroke, renal dialysis, blood oxygenation, and cardiac catheterization.
The compounds of the invention also find utility in a method for inhibiting the coagulation biological samples, which comprises the administration of a compound of the invention.
The compounds of the present invention may also be used in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this invention may be coadministered along with other compounds typically.prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of the present invention may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. These compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
The biological properties of the compounds of the present invention can be readily characterized by methods that are well known in the art, for example by the in vitro protease activity assays and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters, such as are illustrated in the examples.
Diagnostic applications of the compounds of this invention will typically utilize formulations in the form of solutions or suspensions. In the management of thrombotic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington""s Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention typically will be 3-11, more preferably 5-9 and most preferably 7-8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as orally, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds of this invention may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body""s fluids. For other routes of administration, the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be readily determined by one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
The compounds of the invention can be administered orally or parenterally in an effective amount within the dosage range of about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg and more preferably about 1 to 20 mg/kg on a regimen in a single or 2 to 4 divided daily doses and/or continuous infusion.
Typically, about 5 to 500 mg of a compound or mixture of compounds of this invention, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the like are binders such as acacia, corn starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents like corn starch or aiginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline, or a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
The compounds of the present invention may be synthesized by either solid or liquid phase methods described and referenced in standard textbooks, dr by a combination of both methods. These methods are well known in the art. See, Bodanszky, xe2x80x9cThe Principles of Peptide Synthesisxe2x80x9d, Hafnler, et al., Eds., Springer-Verlag, Berlin, 1984.
Starting materials used in any of these methods are commercially available from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or may be readily synthesized by known procedures.
Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated.
During the synthesis of these compounds, the functional groups of the amino acid derivatives used in these methods are protected by blocking groups to prevent cross reaction during the coupling procedure. Examples of suitable blocking groups and their use are described in xe2x80x9cThe Peptides: Analysis, Synthesis, Biologyxe2x80x9d., Academic Press, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987), the disclosures of which are incorporated herein by reference.
Non-limiting exemplary synthesis schemes are outlined directly below, and specific steps are described in the Examples. The reaction products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. The products may be further purified by column chromatography or other appropriate methods.


Compositions and Formulations
The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
Diagnostic applications of the compounds of this invention will typically utilize formulations such as solution or suspension. In the management of thrombotic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington""s Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinalpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
The compounds of this invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds of this invention may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the factor Xa inhibitors of this invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body""s fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambient of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful.
Typically, about 0.5 to 500 mg of a compound or mixture of compounds of this invention, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent. When a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
In practicing the methods of this invention, the compounds of this invention may be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this inventions may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
The preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use. Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature.
With respect to the coronary arterial vasculature, abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA).
With respect to the venous vasculature, abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure.
The compounds of this present invention, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-organ failure or not), thrombotic thrombocytopenic purpura, thromboangiitis obliterans, or thrombotic disease associated with heparin induced thrombocytopenia, (e) the treatment or prevention of thrombotic complications associated with extracorporeal circulation (e.g. renal dialysis, cardiopulmonary bypass or other oxygenation procedure, plasmapheresis), (f) the treatment or prevention of thrombotic complications associated with instrumentation (e.g. cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve), and (g) those involved with the fitting of prosthetic devices.
Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
Thus the compounds of this invention can be added to or contacted with any medium containing or suspected to contain factor Xa and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal""s blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra corporeal circulation systems and the like.
Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.